Three to five percent of newborns in intensive care units are afflicted with a respiratory distress that makes them refractory to optimal ventilation by artificial means. Inflammation of the lungs is even aggravated by conventional artificial ventilation. Insufficient oxygenation of arterial blood and internal organs, particularly of the brain, results from such conditions. A promising alternative in the treatment of acute respiratory distress syndrome (ARDS) is liquid ventilation using breathable inert liquids. The advantages of this technique are suggested by theoretical considerations and supported by solid experimental evidence, which have been well known for many years.
Liquid ventilation can be achieved in two ways, either as partial (PLV) or total liquid ventilation (TLV). PLV uses a conventional gas ventilator after the lungs have been partially filled with perfluorocarbon (PFC) liquid. This technique requires no special ventilator and has been the subject of clinical studies for many years. However, it is clear that the benefits of liquid ventilation are best achieved by total liquid ventilation, wherein the lungs are completely filled with breathable inert liquid oxygenated by external means. Furthermore, the idea of re-establishing prenatal conditions in diseased lungs of newborns while healing occurs appears to be intuitively sound [Praud J P. (2000) “Le liquide pulmonaire”. In: Dehan M, Micheli J, eds. Le poumon du nouveau-né. Paris: Doin, pp 49-51].
The considerable advantage of liquid ventilation over gaseous ventilation in acute respiratory failure is the possibility, as a result of eliminating the air-liquid interface of the lungs, of recruiting and expanding pathologically non-compliant lung alveoli at much lower pressures. The risk of volo/barotrauma is greatly reduced, alveolar ventilation is more uniform, atelectasis is eliminated, and ventilation/perfusion unevenness is decreased. These benefits have been noted in all studies carried out on animal models of newborn respiratory distress [Hirschl R B, Tooley R, Parent A, Johnson K, Bartlett R H. (1996) “Evaluation of gas exchange, pulmonary compliance, and lung injury during total and partial liquid ventilation in the acute respiratory distress syndrome”, Crit Care Med 24:1001-8; Pedneault C, Renolleau S, Gosselin R, Letourneau P, Praud J P. (1999) “Total liquid ventilation using a modified extra-corporeal gas exchange circuit: preliminary results in lambs”, Pediatr Pulmonol Suppl 18: A241; Hirschl R B et al. (1995) “Liquid ventilation in adults, children and full-term neonates”, Lancet 346:1201-2; Shaffer T H, Douglas P R, Lowe C A, Bhutani V K. (1983) “The effects of liquid ventilation on cardiopulmonary function in preterm lambs”. Pediatr Res 17:303-6; Wolfson M R, Greenspan J S, Deoras K S, Rubenstein S D, Shaffer T H. (1992) “Comparison of gas and liquid ventilation: clinical, physiological, and histological correlates”, J Appl Physiol 72:1024-31].
Perfluorocarbons are most often selected as breathable inert liquids. They are non-toxic, chemically stable and biocompatible. In addition, they have been identified as “ideal” liquids for this purpose, since they diffuse rapidly into respiratory airways, have very low surface tension and are very good solvents for respiratory gases allowing them to provide both oxygenation and efficient removal of CO2 [Clark C, Gollan F, (1966) “Survival of mammals breathing organic liquids equilibrated with oxygen at atmospheric pressure, J Appl Physiol, 21:1755-6, 1966]. PFCs not only “wash” debris and inflammatory molecules from the patient's airways [Wolfson M R, Greenspan J S, Shaffer, T H. (1998) “Liquid-assisted ventilation: an alternative respiratory modality” Pediatr Pulmonol 26: 42-63] but can also be used for administering locally-applied medicines such as pulmonary artery dilators [Wolfson M R, Greenspan J S, Shaffer T H. (1996) “Pulmonary administration of vasoactive substances by perfluorochemical ventilation”, Pediatrics 97:449-55]. A first PFC, perflubron, has been approved for medical use, while others, such as perfluorobutane, are currently being examined by the FDA.
Many types of liquid ventilators have been developed and disclosed in the literature. Generally, clinical studies have been conducted using with systems supplied by gravity, using reservoirs above and below the patients' lungs to bring about inspiration and expiration. A drawback is that this type of system does not enable adequate monitoring and control of all the ventilation parameters.
Research laboratories initially constructed liquid ventilators using costly existing equipments for oxygenation and external circulation. In most of the cases, complex pumping was used, composed of peristaltic pumps, liquid reservoirs and several valves with by-pass systems. A major problem then acknowledged by researchers was to design a user-friendly, simple, efficient, safe and reliable ventilator to bring TLV in an intensive care environment.
In order to decrease the mechanical complexity of liquid ventilators, Hirsch et al. [Hirschl R B, Tooley R, Parent A, Johnson K, Bartlett R H. (1996) “Evaluation of gas exchange, pulmonary compliance, and lung injury during total and partial liquid ventilation in the acute respiratory distress syndrome”, Crit Care Med 24:1001-8] developed a connector with a venturi, which allows both inspiration and expiration without using a by-pass circuit and provides continuous liquid flow throughout the system.
Shaffer et al. [Shaffer, Thomas H., Wolfson, Marla R., Heckman, James L., Hoffman, John, (2000), “Liquid Ventilator”, U.S. Pat. No. 6,105,572, 14 p] subsequently developed a total liquid ventilator using a roller pump to force PFC liquid through a respiration and regeneration closed-loop circuit. However, this type of pump generates a pulsatile flow, which causes oscillation of pressure measurements. Thus, other recently developed ventilators [Sekins K M, Nugent L, Mazzoni M, Flanagan C, Neer L, Rozenberg A, Hoffman J. (1999) “Recent innovations in total liquid ventilation system and component design” Biomed Instrum Technol 33 :277-84; Larrabe J L., Alvarez F J., Gatiasoro Cuesta E., Valls-i-Solers A., Alfonso L F., Arnaiz A., Fernandez M B., Loureiro B., Publicover N G., Roman L., Casle J A., Gomez M A. (2001), “Development of a time-cycled volume-controlled Pressure-limited respirator and lung mechanics system for total liquid ventilation”, IEEE Transactions on Biomedical engineering 48:1134-1144] use a double piston pump, of which one piston is dedicated to inspiration and the other piston to expiration. Both pistons are displaced simultaneously on a single platform.
The gas exchanger is crucial to efficiency of TLV, since it must completely remove CO2 from the PFC liquid and replace it with oxygen before the liquid may be returned to the patient's lungs. And CO2 dissolves more easily than does oxygen in PFC liquid. Therefore, in order to bring about adequate gas exchange, many total liquid ventilators are equipped with a costly external blood oxygenator. This piece of equipment contains a silicone membrane comprised of two walls; the oxygen flows between the two walls of the silicone membrane while the PFC liquid flows on the outside of these walls. A major drawback of this oxygenator is that oils from the silicone are extracted by the PFC liquid, which increases membrane replacement frequency and hence operating cost. In addition, PFC liquid leaks through the silicone membrane to pass into the oxygen stream, resulting in PCF losses and higher operating cost.
In other applications, a combination of an atomizer with a bubbler tube has been developed to replace the membrane oxygenator. The column of this oxygenator consists principally of a long vertical tube into which PFC liquid is sprayed through a nozzle at the top and oxygen is injected at the base through a porous stone. Gas exchange occurs through direct contact between the gas bubbles and the liquid. Efficiency is improved by inserting grids into the column to increase the time of residence of the gas bubbles in the liquid [Sekins K M, Nugent L, Mazzoni M, Flanagan C, Neer L, Rozenberg A, Hoffman J. (1999) “Recent innovations in total liquid ventilation system and component design”, Biomed Instrum Technol 33 :277-84.].
However, the performance of the atomizer-bubbler combination is strongly dependent on gas flow rate. When gas flow rate is insufficient, the porous stone does not generate a uniform flow of bubbles. When too high a flow rate is produced, gas bubbles join together to form a cluster of bubbles, which greatly decreases the gas exchange area. In addition, large amounts of liquid are required to fill the column.
As an alternative to oxygenation systems based on membranes or atomizer-bubbler combinations, Lawrence J. NUGENT developed a new type of liquid-breathing gas exchanger described in International Publication WO 99/62626 dated Mar. 16, 2000. This gas exchanger is composed of a fluid-dispersion unit for projecting a thin film of liquid onto a surface exposed to an oxygen gas stream.
The flow of oxygen through the oxygenator is evacuated, carrying with it both CO2 and PFC liquid vapours. During TLV, significant losses of liquid therefore occur. Multifactorial analysis on the efficiency of the exchangers and the conservation of the liquid during TLV has shown that PFC liquid losses are greater in atomizer-bubbler combinations than in membrane-type gas exchangers [Wolfson M R, Miller T F, Peck G, Shaffer T H. (1999) “Multifactorial analysis of exchanger efficiency and liquid conservation during perfluorochemical liquid-assisted ventilation”. Biomed Instrum Technol. 33 :260-7]. This can be explained largely by an evacuation of atomized PFC liquid outside the oxygenator under the form of small droplets conveyed by the gaseous stream, in addition to evaporation losses.
Losses of PFC liquid must be minimized, both for economic reasons and for the protection of medical equipments not compatible with PFC vapours. To meet with this requirement, a condenser is generally incorporated into the system in order to recover PFC vapours escaping from the oxygenators, without interfering with gas flow.
An alternative to the use of condensers would be to recirculate the gas stream, which could allow practically complete retention of PFC vapours. Faithfull and Shutt [Faithfull and Shunt (1999), “Methods and Apparatus for Closed-Circuit Ventilation Therapy”, U.S. Pat. No. 6,041,777, 26 p] have developed a method and an apparatus for this type of system, which allows prolonged administration of PFC liquid without excessive losses due to evaporation. A drawback is that these method and apparatus require a system for extracting CO2 from the closed-loop circuit.
Health-care personnel are aware that a patient may suffer hyper distension of the lungs or collapse of the respiratory airways as well as incomplete gas diffusion. The ventilator must therefore inform the health-care personnel about the patient's status by means of measurements such as compliance, respiratory airways pressure, lung volume, etc. To meet with this requirement, Shaffer et al. [Shaffer T H, Wolfson M R, Greenspan J S, Rubenstein S D, Stern R G. (1994) “Perfluorochemical liquid as a respiratory medium”, Art Cells Blood Subs Immob Biotech 22:315-326] developed a monitoring process for liquid ventilators, based on a comparison of current conditions with a range of desired values, in order to activate alarms or servo-valves on the network of conduits.
Nevertheless, the problem is more complex than simply determining when to activate an alarm. A continuous measurement of the volume of liquid in the lungs is highly desirable, rather than relying on pressure measurement to indicate errors between the volume of liquid injected into and the volume withdrawn from the lungs. Such errors, even small, could result in decreased or increased residual liquid volume in the lungs on the long term. There is currently no efficient method for continuous measurement of such volume of liquid; for example, measurement of a variation in the patient's weight does not constitute a practical method for implementation in the intensive care units.